There are eight known herpes-type viruses which affect human beings: herpes zoster (chicken pox); herpes simplex virus I & II (cold sores and genital herpes); cytomegalovirus (cytomegalic inclusion disease); Epstein-Barr virus (mononucleosis); human .beta.-lymphotropic virus (also known as human herpes virus VI); human herpes virus VII; and Kaposi's sarcoma herpes virus (KSHV). The herpes viruses are medium-sized viruses containing double-stranded DNA, with a nucleocapsid about 100 nm in diameter surrounded by a lipid-containing envelope. The virion is 150-200 nm in diameter and permits latent infections which last for the life span of the host even when antibodies are present.
Purine-based analogs to treat herpes infections are known and have been described, for example, in U.S. Pat. Nos. 4,808,716 to Holy et al. and U.S. Pat. No. 4,755,516 and 4,897,479 to Tolman et al. The Holy et al. patent relates to 9-(phosphonylmethoxyalkyl)adenines and their use in treating herpes simplex virus, types I & II, while the Tolman et al. disclosures describe a family of 6-substituted purines which are stated to be useful against herpes viruses in general. U.S. Pat Nos. 5,047,533 and 5,532,225 to Reist et al., each of common assignment herewith, also describe purine analogs which have antiviral activity against the Herpes group of viruses.
Phosphonate analogs of nucleotides are also described in R. Engel, Chem. Reviews 77(3):349-367 (1977). Phosphonate compounds which are direct cyclic nucleotide analogs are described in: U.S. Pat. No. 3,446,793 to Jones et al.; U.S. Pat. No. 3,560,478 to Myers et al.; German Patent Publications 2,009,834 and 3,045,375; British Patent Nos. 1,243,213 and 1,243,214; A. Hampton et al., Biochemistry 12:1730-1736 (1973); G. H. Jones et al., J. Am. Chem. Soc. 90:5337-5338 (1968); and J. A. Montgomery et al., J. Med. Chem. 22:109-111 (1979).
Other references of interest include EPO Publication No. 173,624, which discloses 9 (3-phosphono-1-propoxymethyl) guanine as an anti-herpes agent, and A. E. Duke et al., Antiviral Res. 6:299-308 (1986) and E. J. Prisbe et al., J. Med. Chem. 29:671-675 (1986), both of which relate to 9 (3-phosphono-1-hydroxymethyl-1-propoxymethyl) guanine.
The present invention now provides a novel class of antiviral nucleotide analogs. The compounds are enantiomerically pure 2-aminopurine phosphonate analogs. Surprisingly, it has been found that at least one of the isolated enantiomers, the "R" enantiomer, has significant activity against several herpes viruses while displaying no detectable kidney toxicity. Accordingly, the invention also relates to the use of the compounds to treat herpes viral infections. Further, the invention encompasses a method for synthesizing the compounds in enantiomerically pure form.